Patricia Robbins-Furman

Characterization of Potocki-Lupski Syndrome (dup(17)(p11.2p11.2)) and Delineation of a Dosage-Sensitive Critical Interval That Can Convey an Autism Phenotype

The duplication 17p11.2 syndrome, associated with dup(17)(p11.2p11.2), is a recently recognized syndrome of multiple congenital anomalies and mental retardation and is the first predicted reciprocal microduplication syndrome described--the homologous recombination reciprocal of the Smith-Magenis syndrome (SMS) microdeletion (del(17)(p11.2p11.2)). We previously described seven subjects with dup(17)(p11.2p11.2) and noted their relatively mild phenotype compared with that of individuals with SMS. Here, we molecularly analyzed 28 additional patients, using multiple independent assays, and also report the phenotypic characteristics obtained from extensive multidisciplinary clinical study of a subset of these patients. Whereas the majority of subjects (22 of 35) harbor the homologous recombination reciprocal product of the common SMS microdeletion (~3.7 Mb), 13 subjects (~37%) have nonrecurrent duplications ranging in size from 1.3 to 15.2 Mb. Molecular studies suggest potential mechanistic differences between nonrecurrent duplications and nonrecurrent genomic deletions. Clinical features observed in patients with the common dup(17)(p11.2p11.2) are distinct from those seen with SMS and include infantile hypotonia, failure to thrive, mental retardation, autistic features, sleep apnea, and structural cardiovascular anomalies. We narrow the critical region to a 1.3-Mb genomic interval that contains the dosage-sensitive RAI1 gene. Our results refine the critical region for Potocki-Lupski syndrome, provide information to assist in clinical diagnosis and management, and lend further support for the concept that genomic architecture incites genomic instability.

Identification of Uncommon Recurrent Potocki-Lupski Syndrome-Associated Duplications and the Distribution of Rearrangement Types and Mechanisms in PTLS

Nonallelic homologous recombination (NAHR) can mediate recurrent rearrangements in the human genome and cause genomic disorders. Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are genomic disorders associated with a 3.7 Mb deletion and its reciprocal duplication in 17p11.2, respectively. In addition to these common recurrent rearrangements, an uncommon recurrent 5 Mb SMS-associated deletion has been identified. However, its reciprocal duplication predicted by the NAHR mechanism had not been identified. Here we report the molecular assays on 74 subjects with PTLS-associated duplications, 35 of whom are newly investigated. By both oligonucleotide-based comparative genomic hybridization and recombination hot spot analyses, we identified two cases of the predicted 5 Mb uncommon recurrent PTLS-associated duplication. Interestingly, the crossovers occur in proximity to a recently delineated allelic homologous recombination (AHR) hot spot-associated sequence motif, further documenting the common hot spot features shared between NAHR and AHR. An additional eight subjects with nonrecurrent PTLS duplications were identified. The smallest region of overlap (SRO) for all of the 74 PTLS duplications examined is narrowed to a 125 kb interval containing only RAI1, a gene recently further implicated in autism. Sequence complexities consistent with DNA replication-based mechanisms were identified in four of eight (50%) newly identified nonrecurrent PTLS duplications. Our findings of the uncommon recurrent PTLS-associated duplication at a relative prevalence reflecting the de novo mutation rate and the distribution of 17p11.2 duplication types in PTLS reveal insights into both the contributions of new mutations and the different underlying mechanisms that generate genomic rearrangements causing genomic disorders.

SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction.

Juvenile polyposis syndrome (JPS) is caused by heterozygous mutations in either SMAD4 or BMPR1A. Individuals with JPS due to mutations in SMAD4 are at greater risk to manifest signs of hereditary hemorrhagic telangiectasia (HHT). HHT is caused by either mutations in SMAD4 or other genes that modulate transforming growth factor‐beta (TGFβ) signaling. Additional genes in the TGFβ network include FBN1, TGFBR1, and TGFBR2, mutations of which cause either Marfan syndrome (MFS) or Loeys–Dietz syndrome (LDS), respectively. As SMAD4, FBN1, and TGFBR1/2 map to different regions of the genome, disorders associated with mutations in these genes are not expected to co‐segregate in a family. We report an individual whose family history was positive for aortopathy, mitral valve dysfunction, and JPS. Mutation analysis of SMAD4 implicates this gene for these phenotypes in this family. Although SMAD4 is among several genes in the TGFβ network, and although prior single case reports have described large vessel aneurysms in HHT, this is the first description of aortic and mitral disease presenting with JPS. This observation suggests that, in addition to HHT, individuals with SMAD4 mutations may be at risk for aortic dilation and mitral valve dysfunction. We emphasize the importance of comprehensive review of the medical history prior to molecular testing, especially in an asymptomatic patient.

Racial-Ethnic Differences in Genetic Amniocentesis Uptake

The objective of this study was to determine the role of health beliefs in genetic amniocentesis acceptance in a diverse racial-ethnic population. Participants completed a previously-validated questionnaire consisting of three sections: (1) demographics, (2) amniocentesis knowledge, and (3) health beliefs, which assessed perceived susceptibility, seriousness of potential impact, benefits of testing, and barriers to testing. The results showed that Hispanic women were less likely to accept amniocentesis (51.5% vs. Caucasian 82.8%, African American 82.9%, Asian 82.8%). Education level was the only demographic factor higher among acceptors. Women who accepted amniocentesis had higher perceived seriousness, susceptibility, and benefits HBM scores and higher knowledge scores than women who declined. HBM scores and knowledge predicted the amniocentesis decision correctly 91.5% of the time. Individual health beliefs and knowledge play a greater role in genetic amniocentesis acceptance than do demographic factors such as race-ethnicity.

Potocki-Lupski Syndrome: A Microduplication Syndrome Associated with Oropharyngeal Dysphagia and Failure to Thrive

OBJECTIVE Failure to thrive (FTT) is a feature of children with Potocki-Lupski syndrome (PTLS) [duplication 17p11.2]. This study was designed to describe the growth characteristics of 24 subjects with PTLS from birth through age 5 years in conjunction with relevant physical features and swallow function studies. STUDY DESIGN We evaluated 24 individuals with PTLS who were ascertained by chromosome analysis and/or array comparative genome hybridization. Clinical assessments included review of medical records, physical examination, otolaryngological examination, and swallow function studies. Measures of height and weight were converted to Z-scores. RESULTS The mean weight-for-age and weight-for-length Z-scores at birth were lower (P < .01) than the reference standard and did not change with age. A history of poor feeding, hypotonia, and FTT were reported in 92%, 88%, and 71%, respectively. Individuals with hypotonia had lower weight-for-age and body mass index-for-age Z-scores (P = .01). Swallow function studies demonstrated at least one abnormality in all subjects. CONCLUSIONS FTT is common in children with PTLS. We hypothesize that oropharyngeal dysphagia and hypotonia likely contribute to FTT in patients with PTLS and recommend that once a diagnosis is established, the individual be assessed for feeding and growth issues and be availed of oromotor therapy and nutritional services.

Cardiovascular findings in duplication 17p11.2 syndrome.

Purpose:Cardiovascular abnormalities are newly recognized features of duplication 17p11.2 syndrome. In a single-center study, we evaluated subjects with duplication 17p11.2 syndrome for cardiovascular abnormalities.Methods:Twenty-five subjects with 17p11.2 duplication identified by chromosome analysis and/or array-based comparative genomic hybridization were enrolled in a multidisciplinary protocol. In our clinical evaluation of these subjects, we performed physical examinations, echocardiography, and electrocardiography. Three of these subjects were followed up longitudinally at our institution.Results:Cardiovascular anomalies, including structural and conduction abnormalities, were identified in 10 of 25 (40%) of subjects with duplication 17p11.2 syndrome. The most frequent abnormality was dilated aortic root (20% of total cohort). Bicommissural aortic valve (2/25), atrial (3/25) and ventricular (2/25) septal defects, and patent foramen ovale (4/25) were also observed.Conclusion:Duplication 17p11.2 syndrome is associated with structural heart disease, aortopathy, and electrocardiographic abnormalities. Individuals with duplication 17p11.2 syndrome should be evaluated by electrocardiography and echocardiography at the time of diagnosis and monitored for cardiovascular disease over time. Further clinical investigation including longitudinal analysis would likely determine the age of onset and characterize the progression (if any) of vasculopathy in subjects with duplication 17p11.2 syndrome, so that specific guidelines can be established for cardiovascular management.Genet Med 2012:14(1):90–94.

Tetrasomy 13q mosaicism associated with phylloid hypomelanosis and precocious puberty

Various forms of pigmentary dysplasias have been known to be associated with chromosomal mosaicism. One of these disorders, known as phylloid hypomelanosis, has been found to be predominantly associated with abnormalities in chromosome 13. Most of the reported literature involves mosaic trisomy 13 with clinical evidence of abnormal pigmentation in the form of leaf‐like or oblong achromic macules following Blaschkos lines. Here, we report on an 8‐year‐old girl with phylloid hypomelanosis and precocious puberty who was found to have mosaicism for tetrasomy 13q in the form of inverted dup(13)(q21) on her skin fibroblasts as well as peripheral blood karyotype. A higher resolution (244K) chromosomal microarray was done on DNA from skin fibroblasts confirming the breakpoint and gain of distal 13q, which made her tetrasomic for 13q21‐qter. This is the first‐ever reported association of tetrasomy 13q with phylloid hypomelanosis and precocious puberty. Our report further emphasizes the need to exclude any type of abnormalities of chromosome 13 in patients with phylloid hypopigmentation.

Stress and Well-Being Among Parents of Children with Potocki-Lupski Syndrome

Potocki-Lupski syndrome (PTLS) or duplication 17p11.2 syndrome is a newly characterized condition causing a variety of health problems with variable severity, including failure to thrive in infancy and childhood, hypotonia, structural heart anomalies, cognitive impairments, speech and learning difficulties, and autism. Due to its recent clinical characterization little is known about the psychosocial impact of this condition on patients and their families. This study evaluated whether parental psychosocial outcomes were associated with children’s PTLS disease severity. Parents of 58 children with PTLS completed a cross-sectional survey that assessed parental stress, quality of life, and coping skills. Parental functioning was associated with greater severity of feeding difficulty and with lower severity of a cardiovascular defect. Findings from this study highlight potential support needs of parents of children affected by PTLS and suggest ways in which these needs may be addressed.